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Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Responsemechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage. [ABSTRACT FROM AUTHOR]

Group 3 innate lymphoid cells (ILC3s) are vital for defending tissue barriers from invading pathogens. Hypoxia influences the production of intestinal ILC3-derived cytokines by activating HIF. Yet, the mechanisms governing HIF-1α in ILC3s and other innate RORγt+ cells during in vivo infections are poorly understood. In our study, transgenic mice with specific Hif-1a gene inactivation in innate RORγt+ cells (RAG1KO HIF-1α▵Rorc) exhibit more severe colitis following Citrobacter rodentium infection, primarily due to the inability to upregulate IL-22. We find that HIF-1α▵Rorc mice have impaired IL-22 production in ILC3s, while non-ILC3 innate RORγt+ cells, also capable of producing IL-22, remain unaffected. Furthermore, we show that IL-18, induced by Toll-like receptor 2, selectively triggers IL-22 in ILC3s by transcriptionally upregulating HIF-1α, revealing an oxygen-independent regulatory pathway. Our results highlight that, during late-stage C. rodentium infection, IL-18 induction in the colon promotes IL-22 through HIF-1α in ILC3s, which is crucial for protection against this pathogen. [Display omitted] • C. rodentium induces production of IL-18 in colon, which upregulates HIF-1α in ILC3s • IL-18 production in the colon is boosted by TLR2 signaling • HIF-1α promotes IL-22 in ILC3s and not in other innate RORγt+ cells after infection • IL-18 is responsible for the production of IL-22 by colonic ILC3s through HIF-1α HIF-1α is a hypoxia-inducible factor regulating several immune cells in the response against infections. Valle-Noguera et al. evaluates the function of HIF-1α in colonic ILC3s during C. rodentium infection in mice, demonstrating that TLR2-induced IL-18 transcriptionally upregulates HIF-1α in ILC3s, boosting IL-22 secretion to protect against the infection. [ABSTRACT FROM AUTHOR]

Bacterial phagocytosis and antigen cross-presentation to activate CD8+ T cells are principal functions of professional antigen presenting cells. However, conventional CD4+ T cells also capture and kill bacteria from infected dendritic cells in a process termed transphagocytosis (also known as transinfection). Here, we show that transphagocytic T cells present bacterial antigens to naive CD8+ T cells, which proliferate and become cytotoxic in response. CD4+ T-cell-mediated antigen presentation also occurs in vivo in the course of infection, and induces the generation of central memory CD8+ T cells with low PD-1 expression. Moreover, transphagocytic CD4+ T cells induce protective anti-tumour immune responses by priming CD8+ T cells, highlighting the potential of CD4+ T cells as a tool for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The leukocyte activation marker CD69 functions as a negative regulator of the immune response, both in NK-dependent tumor rejection and in the inflammation associated with lymphocyte-dependent collagen-induced arthritis. In contrast, it has been reported that CD69-deficient mice are refractory to the neutrophil-dependent acute inflammatory response associated with anti-type II collagen antibody-induced arthritis (CAIA), suggesting a positive regulatory role for CD69 in neutrophil function during arthritis induction. To clarify this discrepancy, the CAIA response was independently analyzed in our CD69-deficient mice. In these experiments, the inflammatory response was unaffected by CD69 deficiency. Additionally, the in vivo down-regulation of CD69 expression by treatment of wild-type mice with the anti-CD69 mAb 2.2, which mimics the CD69-deficient phenotype, did not affect the course of arthritis in this model. Moreover, down-regulation of CD69 expression increased expression in arthritic joints of key inflammatory mediators, including IL-1β, IL-6 and the chemokine MCP-1. Neutrophil accumulation in zymosan-treated air pouches and in thioglycolate-treated peritoneal cavities was also unaffected in CD69-deficient mice. In addition, CD69 expression was absent in activated neutrophils. Taken together, these results rule out a significant stimulatory role for CD69 in acute inflammatory responses mediated by neutrophils. [ABSTRACT FROM AUTHOR]